Derivation and external validation of mass spectrometry-based proteomic model using machine learning algorithms to predict plaque rupture in patients with acute coronary syndrome.

BACKGROUND: A poor prognosis is associated with atherosclerotic plaque rupture (PR) despite after conventional therapy for patients with acute coronary syndrome (ACS). Timely identification of PR improves the risk stratification and prognosis of ACS patients. METHODS: A derivation cohort of 110 patients with ACS who underwent pre-intervention optical coherence tomography (OCT) were matched 1:1 to the PR and intact fibrous cap (IFC) groups according to traditional risk factors. Candidate PR proteins were identified via mass spectrometry (MS)-based proteomics using unbiased machine learning methods and were further validated by enzyme-linked immunosorbent assay (ELISA) in an external validation cohort of 85 patients with ACS. The performance of candidate biomakers was assessed using the receiver operating characteristic curve analysis. RESULTS: 1121 proteins were identified and 535 filtered proteins were used for analysis. Nine candidate proteins were screened by five machine learning algorithms. Three proteins (APOC3, RAB39A, and KNG1) were significantly different between the PR and IFC in validation cohort. The performance of plasm APOC3, RAB39A, and KNG1 for differentiating PR and IFC was superior to that of the conventional biomarkers and risk factors. CONCLUSION: The proteins (APOC3, RAB39A, and KNG1) serve as a potential novel diagnostic tool to identify PR in ACS patients.

Atroposelective Synthesis of Biaryl N-Oxides via Cu-Catalyzed De Novo Heteroaromatic N-Oxide Ring Formation.

Heteroaromatic N-oxides, renowned for their highly polar N─O bond and robust structure, exhibit significant bioactivities and have played a pivotal role in various drug development projects since the discovery of Minoxidil. Moreover, heteroaromatic N-oxides, featuring axially chiral biaryl frameworks, are indispensable as Lewis base catalysts and ligands in organic synthesis. Despite their importance, synthesizing these chiral compounds is challenging, necessitating chiral starting materials or resolution processes. Catalytic strategies rely on the functionalization of heteroaromatic N-oxide compounds, leading to products with a relatively limited skeletal diversity. This study introduces a Cu-catalyzed atroposelective method for synthesizing biaryl N-oxides via de novo heteroaromatic N-oxide ring formation. This mild and efficient approach achieves excellent stereoselectivities (up to 99:1 er), enabling the production of a wide array of N-oxides with novel heteroaromatic scaffolds. The axially chiral N-oxide product 3f demonstrates high stereoselectivity and recyclability as a Lewis base catalyst. Additionally, product 3e exhibits promising therapeutic efficacy against triple-negative breast cancer, with IC50 values of 4.8 and 5.2 µm in MDA-MB-231 and MDA-MB-468 cells, respectively. This research not only advances the synthesis of challenging chiral heteroaromatic N-oxides but also encourages further exploration of N-oxide entities in the discovery of bioactive small molecules.

A Patient With Hepatocellular Carcinoma and Lung Metastasis Successfully Underwent Curative Surgery Following the Downstaging Treatment: A Case Report.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Hepatic resection constitutes the major curative treatment option, but a significant proportion of patients are not surgical candidates on initial evaluation. Along with the development of novel therapeutic strategies including targeted therapies and immunotherapies, a few HCCs can achieve tumor downstaging and be curatively resected. A 52-year-old man was diagnosed with HCC with portal vein invasion and extensive pulmonary and lymph node metastasis. Transarterial chemoembolization (TACE) in conjunction with donafenib and sintilimab was given. Primary tumors in the liver largely shrank with almost complete elimination of the lung metastases following treatment. The patient subsequently underwent curative surgery for HCC, and the pathological examination revealed complete necrosis of the tumor. Targeted immunotherapy was continued after surgery and no disease progression was found on the latest follow-up. Advanced HCC with distant metastasis might have an excellent response to combination therapy of TACE with tyrosine kinase-targeted inhibitors and PD-1 blocker, and achieve opportunity for curative surgery. This efficacy may be associated with the remodeling of immune microenvironment and angiogenesis. HCC is extremely heterogeneous, and the response to therapeutics varies among patients. There is a lack of useful biomarkers to predict therapeutic efficacy, which needs further studies.

Association Between Hemoglobin-to-Red Blood Cell Distribution Width Ratio and 30-Day Mortality in Patients with Acute Pancreatitis: Data from MIMIC-III and MIMIC-IV.

To investigate the relationship between hemoglobin-to-red blood cell distribution width (RDW) ratio (HRR) and the 30-day mortality risk in acute pancreatitis (AP), and assess the predictive ability of HRR. Data from 2001 to 2019 in the Medical Information Mart for Intensive Care-III/IV (MIMIC-III/IV) were analyzed. The outcome of this retrospective cohort study was 30-day mortality. Hemoglobin-to-RDW ratio (0-24 hours) and HRR (24-48 hours) were divided into 4 groups based on quartiles (Q1, Q2, Q3, and Q4). The predictive effect was evaluated by the C-index. A total of 1736 patients were included, and 30-day mortality occurred in 204 (11.75%) patients. Compared with Q1 of HRR (0-24 hours), Q2 (HR = 0.60, 95% CI : 0.42-0.86), Q3 (HR =0.47, 95% CI : 0.31-0.71), and Q4 (HR = 0.45, 95% CI : 0.29-0.68) of HRR levels reduced the 30-day mortality risk. Hemoglobin-to-RDW ratio (24-48 hours) was consistent with the results of HRR (0-24 hours). For changes in HRR, Q4 for changes in HRR levels (HR = 1.64, 95% CI : 1.09-2.45) increased the 30-day mortality risk. Hemoglobin-toRDW ratio significantly improved the predictive effect of Sequential Organ Failure Assessment (C-index = 0.736) and Bedside Index of Severity in Acute Pancreatitis (C-index = 0.704) on 30-day mortality. Higher HRR levels reduced the 30-day mortality risk in AP and may improve the prediction of other tools.

Artificial light at night decreases leaf herbivory in typical urban areas.

Artificial light at night (ALAN) is exerting growing pressure on natural ecosystems, but its impact on biological interactions remains unclear. This study aimed to assess how ALAN influences leaf functional traits and herbivory in two prevalent street tree species (Styphnolobium japonicum (L.) Schott and Fraxinus pennsylvanica) through field surveys and paired experiments in the urban areas of Beijing, China. We found that ALAN led to increased leaf toughness and decreased levels of leaf herbivory. Additionally, ALAN showed species-specific effects on leaf nutrients, size as well as defense substances. The findings illustrate that ALAN can significantly alter some key functional traits and ecological processes (nutrient cycling, energy flow). In general, we suggest that high ALAN intensity will be detrimental to the energy flow from urban plants to higher trophic levels, posing a potential threat to the maintenance of biodiversity (e.g., arthropod diversity, bird diversity) in urban ecosystems.

A near-infrared light-driven Janus nanomotor for deep tumor penetration and enhanced tumor immunotherapy.

A near-infrared light-driven Janus nanomotor is constructed by collagenase-coated gold nanorods and chitosan-functionalized mesoporous organosilica nanoparticles with Mn2+ as the bridging ion. The nanomotors with excellent motility and collagenase activity can potently penetrate into tumors to sufficiently activate innate immune responses, significantly enhancing anti-tumor immune efficacy in vivo.

A gene regulatory network-aware graph learning method for cell identity annotation in single-cell RNA-seq data.

Cell identity annotation for single-cell transcriptome data is a crucial process for constructing cell atlases, unraveling pathogenesis, and inspiring therapeutic approaches. Currently, the efficacy of existing methodologies is contingent upon specific data sets. Nevertheless, such data are often sourced from various batches, sequencing technologies, tissues, and even species. Notably, the gene regulatory relationship remains unaffected by the aforementioned factors, highlighting the extensive gene interactions within organisms. Therefore, we propose scHGR, an automated annotation tool designed to leverage gene regulatory relationships in constructing gene-mediated cell communication graphs for single-cell transcriptome data. This strategy helps reduce noise from diverse data sources while establishing distant cellular connections, yielding valuable biological insights. Experiments involving 22 scenarios demonstrate that scHGR precisely and consistently annotates cell identities, benchmarked against state-of-the-art methods. Crucially, scHGR uncovers novel subtypes within peripheral blood mononuclear cells, specifically from CD4+ T cells and cytotoxic T cells. Furthermore, by characterizing a cell atlas comprising 56 cell types for COVID-19 patients, scHGR identifies vital factors like IL1 and calcium ions, offering insights for targeted therapeutic interventions.

Assessment of the Corneal Biomechanical Features of Sturge-Weber Syndrome Using Dynamic Ultrahigh-speed Scheimpflug Imaging.

PURPOSE: To evaluate the corneal biomechanical characteristics of eyes with Sturge-Weber syndrome (SWS) secondary glaucoma (SSG) by analyzing corneal biomechanical parameters obtained using the Corneal Visualization Scheimpflug Technology instrument (Corvis ST). METHODS: In patients with SWS, eyes affected by SSG were designated as the SSG group while the contralateral eyes were designated as the SWS contralateral group (SC group). Patients from the myopia clinic served as the control group. Dynamic corneal response parameters (DCRs) including the stress-strain index (SSI)-a critical material stiffness parameter that excludes interference from IOP and central corneal thickness (CCT)-were analyzed. RESULTS: For CCT, no significant difference was observed between the SSG and SC groups. However, significant differences were found between the SSG and control groups and between the SC and control groups. Parameters such as HC Time, A1 Deformation Amp., A2 Deformation Amp., length of Whole Eye Movement (WEM), DA Ratio Max (2 mm), PachySlope, DA Ratio Max (1 mm), and ARTh showed significant differences between the SSG group and control group. In the SSG group, 4 of night eyes had an SSI of less than 0.85. CONCLUSIONS: Some DCRs indicated a stiffer cornea in the SSG group, possibly due to a thicker cornea in this group. On analyzing SSI, it was found that corneal material properties change, becoming less stiff in some of the patients with SSG. In conclusion, our study provides a preliminary exploration of the biomechanical properties of SWS secondary glaucoma.

The relationship between nocturia and suicidal ideation: A study on The National Health and Nutrition Survey data.

OBJECTIVES: The focus of this research was to explore any potential link between nocturia and the risk of suicidal ideation. METHODS: Drawing from the National Health and Nutrition Survey, data relating to 25 241 participants was scrutinized. This included 13 421 individuals identifying as male and 11 820 individuals identifying as female. Participants provided information on nocturia and suicidal ideation via self-completed questionnaires. To determine if nocturia was independently related to suicidal ideation, a multivariable logistic regression analysis was employed. Analyses were also undertaken separately for adult males and females. RESULTS: It was found that around 3.5% of participants had experienced suicidal ideation. The results indicated that nocturia increased the risk for suicidal ideation in all adult groups (odds ratio [OR] = 1.67, 95% confidence interval[CI]: 1.37-2.03, p < 0.0001), including both males (OR = 1.91, 95% CI: 1.38-2.65, p < 0.001) and females (OR = 1.48, 95% CI: 1.158-1.90, p = 0.002). The risk for suicidal ideation increased with the severity of nocturia, with significant trends observed in adult males (p for trend = 0.04) and adult females (p for trend = 0.01). Additionally, subgroup examination showed a significant interaction between nocturia and educational level in adult males (p for interaction = 0.03). Among adult females, a noteworthy interaction was observed between nocturia and body mass index (p for interaction = 0.02). CONCLUSION: The research uncovered a connection between nocturia and an elevated risk of suicidal ideation.

Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models.

Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.

Cpne1 deficiency preserves sperm motility under Ca2+ channel blockade.

Calcium ions (Ca2+) play crucial roles in sperm motility and fertilization. The copine (CPNE) family comprises several Ca2+-dependent phospholipid-binding proteins. Of these, CPNE1 is extensively expressed in mammalian tissues; however, its precise role in testicular development and spermatogenesis is yet to be fully characterized. In this study, we used proteomics to analyze testicular biopsies and found that levels of CPNE1 were significantly reduced in patients with non-obstructive azoospermia (defective spermatogenesis) compared to those in patients with obstructive azoospermia (physiological spermatogenesis). In mice, CPNE1 is expressed at various stages of germ cell development and is associated with the Golgi apparatus. Ultimately, CPNE1 is expressed in the flagella of mature sperms. To further examine the role of CPNE1, we developed a Cpne1 knockout mouse model. Analysis showed that the loss of Cpne1 did not impair testicular development, spermatogenesis, or sperm morphology and motility in physiological conditions. When treated with gadolinium (III) chloride or 2-aminoethoxydiphenyl borate, known inhibitors of store-operated Ca2+ entry, Ca2+ signals and sperm motility were significantly compromised in wild-type mice; however, both mechanisms were conserved in KO mice. These results suggested that CPNE1 is dispensable for testicular development, spermatogenesis or sperm motility in physiological conditions. In addition, CPNE1 may represent a target of Ca2+ channel inhibitors and may therefore be implicated in the regulation of Ca2+ signaling and sperm motility.

Plasma biomarkers in patients with familial cavernous malformation and their first-degree relatives.

Background: We aimed to explore the differences in plasma biomarker levels between patients with familial cerebral cavernous malformations (FCCM) and their healthy first-degree relatives (FDRs) and between FCCM patients with and without severe chronic disease aggressiveness (CDA). Methods: Magnetic resonance imaging (MRI) scanning and genetic testing was performed in patients with multiple CCMs and their FDRs. Sixty-seven plasma biomarkers were tested using a customised multiplex bead immunoassay kit. Univariate and multivariate unconditional logistic regression analyses were conducted to determine the associations between plasma factors and the risk of developing FCCM and severe CDA. Receiver operating characteristic (ROC) curves were generated for each independent risk factor. Results: Plasma factors of 37 patients with FCCM and 37 FDRs were examined. Low CD31 (P < 0.001) and BDNF levels (P = 0.013) were independent risk factors for FCCM. The best model was achieved by combining the results of CD31 and BDNF (AUC = 0.845, sensitivity 0.838, specificity 0.784, cutoff score - 4.295) to distinguish patients with FCCM from healthy FDRs. Low serpin E1/PAI-1 (P = 0.011) and high ROBO4 levels (P = 0.013) were independent risk factors for severe CDA in patients with FCCM. The best model was achieved by combining the results of E1/PAI-1 and ROBO4 levels (AUC = 0.913, sensitivity 1.000, specificity 0.760, cutoff score - 0.525) to identify patients with FCCM and severe CDA. Conclusions: The plasma concentrations of CD31 and BDNF seem to be lower in patients with FCCM than in their healthy FDRs. Low serpin E1/PAI-1 and high ROBO4 concentrations may be correlated with high lesion burden and risk of recurrent bleeding.

Circulating B Cell-Derived Small RNA Delivered by Extracellular Vesicles: A Dialogue Mechanism for Long-Range Targeted Renal Mitochondrial Injury in Obesity.

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3-CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions.

Bromodomain Protein Inhibition Protects ß-Cells from Cytokine-Induced Death and Dysfunction via Antagonism of NF-κB Pathway.

Cytokine-induced ß-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect ß-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (bromo- and extra-terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on ß-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected ß-cells from cytokine-induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced ß-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in ß-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for ß-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting ß-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving ß-cell functional mass in T1D.

SENP2 promotes ESCC proliferation through SETDB1 deSUMOylation and enhanced fatty acid metabolism.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and its metabolic reprogramming mechanism remains unclear. Small ubiquitin-like modifier(SUMO) -specific protease(SENP2) is highly related to fatty acids metabolism in some normal tissue. Thus, this study investigates the correlation between SENP2 and ESCC, and the possible mechanism. SENP2 expression was up-regulated in ESCC tissues compared to normal tissues, with high levels associated with poor overall survival rates. Knockdown of SENP2 inhibited ESCC proliferation, fatty acid uptake, and oxidation in vitro. RNA-seq indicated that SENP2 upregulated PPARγ, CPT1A, ACSL1, and CD36, through the deSUMOylation of SETDB1. SENP2 promotes ESCC proliferation and enhances fatty acid uptake and oxidation. High expression of SENP2 may be a poor prognostic biomarker for ESCC patients.

Advances and challenges in molecular engineering of 2D/3D perovskite heterostructures.

Organic-inorganic hybrid perovskites have been intensively studied in past decades due to their outstanding performance in solar cells and other optoelectronic devices. Recently, the emergence of two-dimensional/three-dimensional (2D/3D) heterojunctions have enabled many solar cell devices with >25% power conversion efficiency, driven by advances in our understanding of the structural and photophysical properties of the heterojunctions and our ability to control these properties through organic cation configuration in 2D perovskites. In this feature article, we discuss a fundamental understanding of structural characteristics and the carrier dynamics in the 2D/3D heterojunctions and their impact factors. We further elaborate the design strategies for the molecular configuration of organic cations to achieve thorough management of these properties. Finally, recent advances in 2D/3D heterostructures in solar cells, light-emitting devices and photodetectors are highlighted, which translate fundamental understandings to device applications and also reveal the remaining challenges in ligand design for the next generation of stable devices. Future development prospects and related challenges are also provided, with wide perspectives and insightful thoughts.

Sequential Manipulation Against Rank Aggregation: Theory and Algorithm.

Rank aggregation with pairwise comparisons is widely encountered in sociology, politics, economics, psychology, sports, etc. Given the enormous social impact and the consequent incentives, the potential adversary has a strong motivation to manipulate the ranking list. However, the ideal attack opportunity and the excessive adversarial capability cause the existing methods to be impractical. To fully explore the potential risks, we leverage an online attack on the vulnerable data collection process. Since it is independent of rank aggregation and lacks effective protection mechanisms, we disrupt the data collection process by fabricating pairwise comparisons without knowledge of the future data or the true distribution. From the game-theoretic perspective, the confrontation scenario between the online manipulator and the ranker who takes control of the original data source is formulated as a distributionally robust game that deals with the uncertainty of knowledge. Then we demonstrate that the equilibrium in the above game is potentially favorable to the adversary by analyzing the vulnerability of the sampling algorithms such as Bernoulli and reservoir methods. According to the above theoretical analysis, different sequential manipulation policies are proposed under a Bayesian decision framework and a large class of parametric pairwise comparison models. For attackers with complete knowledge, we establish the asymptotic optimality of the proposed policies. To increase the success rate of the sequential manipulation with incomplete knowledge, a distributionally robust estimator, which replaces the maximum likelihood estimation in a saddle point problem, provides a conservative data generation solution. Finally, the corroborating empirical evidence shows that the proposed method manipulates the results of rank aggregation methods in a sequential manner.

Adhesion and Transparency Enhancement between Flexible Polyimide-PDMS Copolymerized Film and Copper Foil for LED Transparent Screen.

With the increasing demand for innovative electronic products, LED transparent screens are gradually entering the public eye. Polyimide (PI) materials combine high temperature resistance and high transparency, which can be used to prepare flexible copper-clad laminate substrates. The physical and chemical properties of PI materials differ from copper, such as their thermal expansion coefficients (CTEs), surface energy, etc. These differences affect the formation and stability of the interface between copper and PI films, resulting in a short life for LED transparent screens. To enhance PI-copper interfacial adhesion, aminopropyl-terminated polydimethylsiloxane (PDMS) can be used to increase the adhesive ability. Two diamine monomers with a trifluoromethyl structure and a sulfone group structure were selected in this research. Bisphenol type A diether dianhydride is a dianhydride monomer. All three of the above monomers have non-coplanar structures and flexible structural units. The adhesion and optical properties can be improved between the interface of the synthesized PI films and copper foil. PI films containing PDMS 0, 1, 3, and 5 wt% were analyzed using UV spectroscopy. The transmittance of the PI-1/3%, PI-1/5%, PI-2/3%, and PI-2/5% films were all more than 80% at 450 nm. Meanwhile, the Td 5% and Td 10% heat loss and Tg temperatures decreased gradually with the increase in PDMS. The peel adhesion of PI-copper foil was measured using a 180° peel assay. The effect of PDMS addition on peel adhesion was analyzed. PIs-3% films had the greatest peeling intensities of 0.98 N/mm and 0.85 N/mm.

Moiré superlattices in twisted two-dimensional halide perovskites.

Moiré superlattices have emerged as a new platform for studying strongly correlated quantum phenomena, but these systems have been largely limited to van der Waals layer two-dimensional materials. Here we introduce moiré superlattices leveraging ultrathin, ligand-free halide perovskites, facilitated by ionic interactions. Square moiré superlattices with varying periodic lengths are clearly visualized through high-resolution transmission electron microscopy. Twist-angle-dependent transient photoluminescence microscopy and electrical characterizations indicate the emergence of localized bright excitons and trapped charge carriers near a twist angle of ~10°. The localized excitons are accompanied by enhanced exciton emission, attributed to an increased oscillator strength by a theoretically predicted flat band. This research showcases the promise of two-dimensional perovskites as unique room-temperature moiré materials.